Ectopic expression of murine CD47 minimizes macrophage rejection of human hepatocyte xenografts in immunodeficient mice.

2.50
Hdl Handle:
http://hdl.handle.net/10033/251441
Title:
Ectopic expression of murine CD47 minimizes macrophage rejection of human hepatocyte xenografts in immunodeficient mice.
Authors:
Waern, Johan M; Yuan, Qinggong; Rüdrich, Urda; Becker, Pablo D; Schulze, Kai; Strick-Marchand, Helene; Huntington, Nicholas D; Zacher, Behrend J; Wursthorn, Karsten; Disanto, James P; Guzman, Carlos A; Manns, Michael P; Ott, Michael; Bock, Michael
Abstract:
Macrophages play an important role in the rejection of xenogeneic cells and therefore represent a major obstacle to generating chimeric mice with human xenografts that are useful tools for basic and preclinical medical research. The signal inhibitory regulatory protein α (SIRPα) receptor is a negative regulator of macrophage phagocytic activity and interacts in a species-specific fashion with its ligand CD47. Furthermore, SIRPα polymorphism in laboratory mouse strains significantly affects the extent of human CD47-mediated toleration of human xenotransplants. Aiming to minimize macrophage activity and thus optimize human cell engraftment in immunodeficient mice, we lentivirally transduced murine CD47 (Cd47) into human liver cells. Human HepG2 liver cells expressing Cd47 were less frequently contacted and phagocytosed by murine RAW264.7 macrophages in vitro than their Cd47-negative counterparts. For the generation of human-mouse chimeric livers in immunodeficient BALB-ΔRAG/γ(c) -uPA (urokinase-type plasminogen activator) mice, freshly thawed cryopreserved human hepatocytes were transduced with a lentiviral expression vector for Cd47 using a refined in vitro transduction protocol immediately before transplantation. In vivo, Cd47-positive human primary hepatocytes were selectively retained following engraftment in immunodeficient mice, leading to at least a doubling of liver repopulation efficiencies. Conclusion: We conclude that ectopic expression of murine Cd47 in human hepatocytes selectively favors engraftment upon transplantation into mice, a finding that should have a profound impact on the generation of robust humanized small animal models. Moreover, dominance of ectopically expressed murine Cd47 over endogenous human CD47 should also widen the spectrum of immunodeficient mouse strains suitable for humanization. (HEPATOLOGY 2012).
Affiliation:
Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany; Twincore, Centre for Experimental and Clinical Infection Research, Hannover, Germany; Medical and Oncology Clinic, Södra Älvsborgs Sjukhus, Borås, Sweden.
Citation:
Ectopic expression of murine CD47 minimizes macrophage rejection of human hepatocyte xenografts in immunodeficient mice. 2012, 56 (4):1479-88 Hepatology
Journal:
Hepatology (Baltimore, Md.)
Issue Date:
Oct-2012
URI:
http://hdl.handle.net/10033/251441
DOI:
10.1002/hep.25816
PubMed ID:
22535707
Type:
Article
Language:
en
ISSN:
1527-3350
Appears in Collections:
publications of AG Cell and Gene therapy

Full metadata record

DC FieldValue Language
dc.contributor.authorWaern, Johan Men_GB
dc.contributor.authorYuan, Qinggongen_GB
dc.contributor.authorRüdrich, Urdaen_GB
dc.contributor.authorBecker, Pablo Den_GB
dc.contributor.authorSchulze, Kaien_GB
dc.contributor.authorStrick-Marchand, Heleneen_GB
dc.contributor.authorHuntington, Nicholas Den_GB
dc.contributor.authorZacher, Behrend Jen_GB
dc.contributor.authorWursthorn, Karstenen_GB
dc.contributor.authorDisanto, James Pen_GB
dc.contributor.authorGuzman, Carlos Aen_GB
dc.contributor.authorManns, Michael Pen_GB
dc.contributor.authorOtt, Michaelen_GB
dc.contributor.authorBock, Michaelen_GB
dc.date.accessioned2012-11-08T14:47:05Z-
dc.date.available2012-11-08T14:47:05Z-
dc.date.issued2012-10-
dc.identifier.citationEctopic expression of murine CD47 minimizes macrophage rejection of human hepatocyte xenografts in immunodeficient mice. 2012, 56 (4):1479-88 Hepatologyen_GB
dc.identifier.issn1527-3350-
dc.identifier.pmid22535707-
dc.identifier.doi10.1002/hep.25816-
dc.identifier.urihttp://hdl.handle.net/10033/251441-
dc.description.abstractMacrophages play an important role in the rejection of xenogeneic cells and therefore represent a major obstacle to generating chimeric mice with human xenografts that are useful tools for basic and preclinical medical research. The signal inhibitory regulatory protein α (SIRPα) receptor is a negative regulator of macrophage phagocytic activity and interacts in a species-specific fashion with its ligand CD47. Furthermore, SIRPα polymorphism in laboratory mouse strains significantly affects the extent of human CD47-mediated toleration of human xenotransplants. Aiming to minimize macrophage activity and thus optimize human cell engraftment in immunodeficient mice, we lentivirally transduced murine CD47 (Cd47) into human liver cells. Human HepG2 liver cells expressing Cd47 were less frequently contacted and phagocytosed by murine RAW264.7 macrophages in vitro than their Cd47-negative counterparts. For the generation of human-mouse chimeric livers in immunodeficient BALB-ΔRAG/γ(c) -uPA (urokinase-type plasminogen activator) mice, freshly thawed cryopreserved human hepatocytes were transduced with a lentiviral expression vector for Cd47 using a refined in vitro transduction protocol immediately before transplantation. In vivo, Cd47-positive human primary hepatocytes were selectively retained following engraftment in immunodeficient mice, leading to at least a doubling of liver repopulation efficiencies. Conclusion: We conclude that ectopic expression of murine Cd47 in human hepatocytes selectively favors engraftment upon transplantation into mice, a finding that should have a profound impact on the generation of robust humanized small animal models. Moreover, dominance of ectopically expressed murine Cd47 over endogenous human CD47 should also widen the spectrum of immunodeficient mouse strains suitable for humanization. (HEPATOLOGY 2012).en_GB
dc.language.isoenen
dc.rightsArchived with thanks to Hepatology (Baltimore, Md.)en_GB
dc.titleEctopic expression of murine CD47 minimizes macrophage rejection of human hepatocyte xenografts in immunodeficient mice.en
dc.typeArticleen
dc.contributor.departmentDepartment of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany; Twincore, Centre for Experimental and Clinical Infection Research, Hannover, Germany; Medical and Oncology Clinic, Södra Älvsborgs Sjukhus, Borås, Sweden.en_GB
dc.identifier.journalHepatology (Baltimore, Md.)en_GB

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